Incidence Of Geographic Atrophy Research Articles

Reticular Pseudodrusen Status, ARMS2/HTRA1 Genotype, and Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report 32

To determine whether reticular pseudodrusen (RPD) status, ARMS2/HTRA1 genotype, or both are associated with altered geographic atrophy (GA) enlargement rate and to analyze potential mediation of genetic effects by RPD status. Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. Eyes with GA: n = 771 from 563 participants. Geographic atrophy area was measured from fundus photographs at annual visits. Reticular pseudodrusen presence was graded from fundus autofluorescence images. Mixed-model regression of square root of GA area was performed by RPD status, ARMS2 genotype, or both. Change in square root of GA area. Geographic atrophy enlargement was significantly faster in eyes with RPD (P < 0.0001): 0.379 mm/year (95% confidence interval [CI], 0.329-0.430 mm/year) versus 0.273 mm/year (95% CI, 0.256-0.289 mm/year). Enlargement was also significantly faster in individuals carrying ARMS2 risk alleles (P < 0.0001): 0.224 mm/year (95% CI, 0.198-0.250 mm/year), 0.287 mm/year (95% CI, 0.263-0.310 mm/year), and 0.307 mm/year (95% CI, 0.273-0.341 mm/year) for 0, 1, and 2, respectively. In mediation analysis, the direct effect of ARMS2 genotype was 0.074 mm/year (95% CI, 0.009-0.139 mm/year), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI, -0.006 to 0.009 mm/year). In eyes with incident GA, RPD presence was not associated with an altered likelihood of central involvement (P= 0.29) or multifocality (P= 0.16) at incidence. In eyes with incident noncentral GA, RPD presence was associated with faster GA progression to the central macula (P= 0.009): 157 μm/year (95% CI, 126-188 μm/year) versus 111 μm/year (95% CI, 97-125 μm/year). Similar findings were observed in the Age-Related Eye Disease Study. Geographic atrophy enlargement is faster in eyes with RPD and in individuals carrying ARMS2/HTRA1 risk alleles. However, RPD status does not mediate the association between ARMS2/HTRA1 genotype and faster enlargement. Reticular pseudodrusen presence and ARMS2/HTRA1 genotype are relatively independent risk factors, operating by distinct mechanisms. Reticular pseudodrusen presence does not predict central involvement or multifocality at GA incidence but is associated with faster progression toward the central macula. Reticular pseudodrusen status should be considered for improved predictions of enlargement rate. Proprietary or commercial disclosure may be found after the references.

Cluster Analysis and Genotype–Phenotype Assessment of Geographic Atrophy in Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 25

To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration can be separated into 2 or more partially distinct subtypes and if these have different genetic associations. This is important because distinct GA subtypes associated with different genetic factors might require customized therapeutic approaches. Cluster analysis of participants within a controlled clinical trial, followed by assessment of phenotype-genotype associations. Age-Related Eye Disease Study 2 participants with incident GA during study follow-up: 598 eyes of 598 participants. Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features) and longitudinal analyses (using 14 phenotypic features). The identified clusters were compared by 4 pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse (clustering by genotype and comparison by phenotype). Characteristics and quality of cluster solutions, assessed by Calinski-Harabasz scores, unexplained variance, and consistency; and genotype-phenotype associations, assessed by t test. In cross-sectional phenotypic analyses, k-means identified 2 clusters (labeled A and B), whereas hierarchical clustering identified 4 clusters (C-F); cluster membership differed principally by GA configuration but in few other ways. In longitudinal phenotypic analyses, k-means identified 2 clusters (G and H) that differed principally by smoking status but in few other ways. These 3 sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the 4 genetic risk scores demonstrated no significant differences (P > 0.05 for all). In clustering by genotype, k-means identified 2 clusters (Iand J). These differed principally at ARMS2, but no significant genotype-phenotype associations were observed (P > 0.05 for all). Phenotypic clustering resulted in GA subtypes defined principally by GA configuration in cross-sectional analyses, but these were not replicated in longitudinal analyses. These negative findings, together with the absence of significant phenotype-genotype associations, indicate that GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic causes.

Enlargement of Geographic Atrophy From First Diagnosis to End of Life

Treatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking. To determine long-term enlargement of GA. In this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020. Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. Of 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm2 (95% CI, 3.11-4.67). Enlargement rate varied widely between persons (0.02 to 4.05 mm2 per year), with a mean of 1.09 mm2 per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P = .01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. In this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy.

Progression of Geographic Atrophy with Subsequent Exudative Neovascular Disease in Age-Related Macular Degeneration: AREDS2 Report 24

To examine whether the rate of geographic atrophy (GA) enlargement is influenced by subsequent exudative neovascular age-related macular degeneration (nAMD) and hence, to explore indirectly whether nonexudative nAMD may slow GA enlargement. Post hoc analysis of a controlled clinical trial cohort. Age-Related Eye Disease Study 2 participants 50 to 85 years of age. Baseline and annual stereoscopic color fundus photographs were evaluated for (1) GA presence and area and (2) exudative nAMD presence. Two cohorts were constructed: eyes with GA at study baseline (prevalent cohort) and eyes in which GA developed during follow-up (incident cohort). Mixed-model regression of the square root of GA area was performed according to the presence or absence of subsequent exudative nAMD. Change over time in square root of GA area. Of the 757 eyes in the incident GA cohort, over a mean follow-up of 2.3 years (standard deviation [SD], 1.2 years), 73 eyes (9.6%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was significantly slower (0.20 mm/year; 95% confidence interval [CI], 0.12-0.28 mm/year) compared with the other 684 eyes in which subsequent exudative nAMD did not develop (0.29 mm/year; 95% CI, 0.27-0.30 mm/year; P= 0.037). Of the 456 eyes in the prevalent GA cohort, over a mean follow-up of 4.1 years (SD, 1.4 years), 63 eyes (13.8%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was similar (0.31 mm/year; 95% CI, 0.24-0.37 mm/year) compared with the other 393 eyes in which subsequent exudative nAMD did not develop (0.28 mm/year; 95% CI, 0.26-0.29 mm/year; P= 0.37). In eyes with recent GA, GA enlargement before the development of exudative nAMD seemsslowed. This association was not observed in eyes with more long-standing GA, which have larger lesionsizes. Hence, perilesional nonexudative choroidal neovascular tissue (presumably present before the development of clinically apparent exudation) may slow enlargement of smaller GA lesions through improvedperfusion. Thishypothesis warrants further evaluation in prospective studies.

Precursors and Development of Geographic Atrophy with Autofluorescence Imaging: Age-Related Eye Disease Study 2 Report Number 18

To describe the sequence of events leading to development of geographic atrophy (GA) in age-related macular degeneration with fundus autofluorescence (FAF) imaging. Post hoc analysis of FAF images from the Age-Related Eye Disease Study2. Fundus autofluorescence images of 120 eyes (109 patients) with incident GA and at least 2 years of preceding FAF images. Images of incident GA were stacked and aligned over FAF images of preceding annual visits. The regions of retina where incident GA developed were assessed on prior years' FAF images. These regions, defined as precursor lesions, were classified into minimal change autofluorescence, predominant hypoautofluorescence (decreased autofluorescence), predominant hyperautofluorescence (increased autofluorescence), and mixed autofluorescence. The natural progression in precursor lesions leading to GA formation and their associations with incident GA size and GA enlargement rate were evaluated. Incident GA area and enlargement rate and precursor pattern frequency. Incident GA had a mean area of 1.00 mm2 (range, 0.15-8.22 mm2) and an enlargement rate of 0.97 mm2/year (standard deviation, 1.66 mm2/year). Predominant hypoautofluorescence was the most common precursor lesion, increasing from 42% to 81% over 3 years before onset of GA. Almost 30% of eyes showed minimal change autofluorescence 3 years before GA. Among the other precursors, 70% progressed to predominant hypoautofluorescence before GA developed. The type of precursor lesions was not associated with incident GA area. Geographic atrophy evolving from minimal change autofluorescence precursor lesions was associated with faster GA enlargement rates compared with other precursor lesion classes. Using image registration, we identified changes in autofluorescence images before the onset of GA. Decreased autofluorescence was the most common change, although minimal changes also were seen in one third of the images. Incident GA that arises from predominantly normal autofluorescence is associated with faster enlargement rates compared with GA arising from abnormal autofluorescence. Faster GA enlargement rates also were associated with incident GA size, area of surround abnormal autofluorescence, and presence of reticular pseudodrusen.

Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16

To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Prospective cohort study within a controlled clinical trial. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. (1) Presence or development of GA; (2) change in the square root of GA area over time. At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P= 0.33) or smoking status (P= 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P= 0.0002), and APOE non-risk (P= 0.001) genotypes. Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Progression and Incidence of Geographic Atrophy in Patients with Wet Age-Related Macular Degeneration undergoing Anti- VEGF Therapy

Importance: Age Related Macular Degeneration (AMD) is one of the leading causes of blindness in the developed world. There are two phenotypes of AMD as defined by the United Kingdom Department of Health: neovascular AMD (nAMD) and geographic atrophy (GA). GA can develop after nAMD as well. There is recent evidence of the development of GA after anti-vascular endothelial growth factor (anti-VEGF) treatment. Our study aims to assess the percentage, risk factors and characteristics of patients developing GA after the different anti-VEGF medications for nAMD. Observations: We retrospectively reviewed case records of 1415 eyes diagnosed with nAMD treated with anti-VEGF for a period of 60 months. Pre and post anti-VEGF treatment characteristics were recorded. Main outcome measures were the number of patients that developed GA after treated for nAMD with aflibercept, ranibizumab and bevaciumab. Secondary outcome measures included the following: number of injections per type, mean change in the best corrected visual acuity (BCVA), area of GA, central macular thickness (CMT), and the proportion of patients showing change in intra- retinal fluid (IRF), sub-retinal fluid (SRF) and pigment epithelial detachment (PED). 109 eyes (7.7%) developed GA after the last assessment. The number of injections was significantly related to the development of GA, R2=0.000246358, P<0.01. Other studied variables could not significantly predict development or progression of GA. Conclusion and relevance: In the era of antiVEGF for nAMD treatment, we need to take into account the risk of excessive treatment. Considering GA treatment is still under research the perfect balance between treatment and withholding still needs to be found. In addition other associations or risk factors for GA development after anti-VEGF need to be researched.

Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Retinal Angiomatous Proliferation: A Review of the Literature and Therapeutic Considerations

Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (AMD). In the past, this peculiar type of neovascularization was considered to be refractory to treatment, and the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in RAP was not thoroughly evaluated in the early clinical trials. However, more recent studies focusing on treatment outcomes in RAP have shown that visual acuity can be improved or at least maintained in the majority of eyes using anti-VEGF therapy. Favorable results were achieved regardless of the regimens used which included fixed-dosing, as-needed, and treat-and-extend regimens. Nowadays, anti-VEGF therapy is a widely used first-line therapy for RAP. RAP shows several characteristics that distinguish it from other subtypes of neovascular AMD. The choroid is usually very thin and the incidence of geographic atrophy or retinal pigment epithelial tear is relatively high in RAP compared to the other subtypes. It is helpful for clinicians to consider these characteristics, which may influence the treatment outcome. In this article, the results of previous studies on anti-VEGF therapy for RAP are reviewed and important therapeutic considerations are discussed.

Incidence and Growth of Geographic Atrophy during 5 Years of Comparison of Age-Related Macular Degeneration Treatments Trials

To estimate the incidence, size, and growth rate of geographic atrophy (GA) during 5 years of follow-up among participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Cohort within a clinical trial. Participants included in CATT. A total of 1185 CATT participants were randomly assigned to ranibizumab or bevacizumab treatment and to 3 treatment regimens. Participants were released from protocol treatment at 2 years and examined at approximately 5 years (N= 647). Two masked graders assessed the presence and size of GA in digital color photographs (CPs) and fluorescein angiograms (FAs) taken at baseline and years 1, 2, and 5. Cox proportional hazard models were used to identify risk factors for incidence of GA. Annual change in the square root of the total area of GA was the measure of growth. Multivariate linear mixed models including baseline demographic, treatment, and ocular characteristics on CP/FA and optical coherence tomography (OCT) as candidate risk factors were used to estimate adjusted growth rates, standard errors (SEs), and 95% confidence intervals (CIs). Geographic atrophy incidence and growth rate. Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years. At baseline, older age, hypercholesterolemia, worse visual acuity, larger choroidal neovascularization (CNV) area, retinal angiomatous proliferation (RAP) lesion, GA in the fellow eye, and intraretinal fluid were associated with a higher risk of incident GA. Thicker subretinal tissue complex and presence of subretinal fluid were associated with less GA development. The overall GA growth rate was 0.33 mm/year (SE, 0.02 mm/year). Eyes treated with ranibizumab in the first 2 years of the clinical trial had a higher growth rate than eyes treated with bevacizumab (adjusted growth rate, 0.38 vs. 0.28 mm/year; P= 0.009). Geographic atrophy in the fellow eye, hemorrhage, and absence of sub-retinal pigment epithelium fluid at baseline were associated with a higher growth rate. Development of GA is common 5 years after initiating therapy. Several risk factors identified at 2 years of follow-up persist at 5 years of follow-up.

Pseudodrusen and Incidence of Late Age-Related Macular Degeneration in Fellow Eyes in the Comparison of Age-Related Macular Degeneration Treatments Trials

To evaluate the association between pseudodrusen and incidence of late age-related macular degeneration (AMD) in fellow eyes of patients with unilateral neovascular AMD (nAMD). Cohort study within the Comparison of AMD Treatments Trials (CATT). Patients with neither nAMD nor geographic atrophy (GA) in the fellow eye at baseline. Presence and type (dot, reticular, or confluent) of baseline pseudodrusen were assessed using digital color fundus photography (CFP) viewed under full color, green channel, and blue channel; red-free images; and fluorescein angiography (FA). Incidence of nAMD was based on monthly clinical examination and reading center evaluation of images at years 1 and 2. Incidence of GA was based on reading center evaluation of CFP and FA images at years 1 and 2. Associations of baseline pseudodrusen with incident nAMD and GA were summarized with adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs) from multivariate Cox models, with adjustment of covariates identified through backward stepwise selection. Incident nAMD and GA. Among 620 fellow eyes, 176 (28.4%) had baseline pseudodrusen (55% dot, 82% reticular, 35% confluent). Within 2 years, nAMD occurred in 54 eyes (30.7%) with pseudodrusen and in 72 eyes (16.2%) without pseudodrusen (aRR, 2.05; 95% CI, 1.43-2.93); GA occurred in 27 eyes (15.3%) with pseudodrusen and in 37 eyes (8.3%) without pseudodrusen (aRR, 1.89; 95% CI, 1.13-3.17); late AMD occurred in 73 eyes (41.5%) with pseudodrusen and in 101 eyes (22.8%) without pseudodrusen (aRR, 2.07; 95% CI, 1.51-2.83). Dot pseudodrusen were associated independently with nAMD (aRR, 2.53; 95% CI, 1.60-4.00), whereas confluent pseudodrusen were associated independently with GA (aRR, 4.35; 95% CI, 1.69-11.2). Eyes with pseudodrusen had increased incidence of late AMD regardless of whether the Age-Related Eye Diseases Study (AREDS) severity score was 2 (28.7% vs. 10.3%), 3 (34.9% vs. 13.7%), or 4 (50.5% vs. 32.0%). In fellow eyes of CATT participants, pseudodrusen were associated independently with a higher incidence of both nAMD and GA. Dot pseudodrusen were associated with nAMD, whereas confluent pseudodrusen were associated with GA. Pseudodrusen should be considered along with the AREDS severity score for predicting late AMD.

Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study

There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but few studies have explored associations with folate and B vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value. We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility. Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII α 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses. There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD. High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. This trial was registered at clinicaltrials.gov as NCT00594672.

Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration: A Meta-Analysis.

ImportanceThe fellow eye of patients with unilateral neovascular age-related degeneration (nAMD) is at increased risk of developing late AMD. Several cohort studies have evaluated the prevalence of pseudodrusen and the association between pseudodrusen and late AMD in the fellow eye of patients with unilateral nAMD. However, these studies have limited sample sizes and their results are inconsistent.ObjectiveTo evaluate the prevalence rate of pseudodrusen, and the association between pseudodrusen and incidence of late AMD (nAMD and geographic atrophy (GA)) in the fellow eye of patients with unilateral nAMD.Data SourcesThe PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to July 2015, as well as other systematic reviews.Study SelectionAll cohort studies for pseudodrusen with late AMD in the fellow eye of patients with unilateral nAMD.Data Extraction and SynthesisThe numbers of patients with and without pseudodrusen at baseline and the numbers of incident nAMD and GA during follow up among patients with and without pseudodrusen were independently extracted by 2 authors. The results were pooled using random-effects meta-analysis. Heterogeneity was assessed using the I2 test.Main Outcome MeasuresPrevalence rate of pseudodrusen, risk ratios (RRs) and their 95% confidence intervals (95% CIs) for associations between pseudodrusen and the incidence of nAMD and GA in the fellow eye.ResultsFive cohort studies (N = 677 patients) from 8 countries across 4 continents were included. The pooled prevalence rate of pseudodrusen in the fellow eye was 48.1% (95% Cl: 36.7–59.5%, I2 = 87%). Pseudodrusen were associated with an increased risk of nAMD (RR = 1.54, 95% Cl: 1.10–2.16, I2 = 42%), GA (RR = 4.70, 95% Cl: 1.22–18.1, I2 = 64%), and late AMD (RR = 2.03, 95% Cl: 1.35–3.06, I2 = 60%).ConclusionsFor patients with unilateral nAMD, pseudodrusen were present in about half of the fellow eyes. The presence of pseudodrusen was associated with a 1.5 times higher risk of developing nAMD, a 4.7 times higher risk of developing GA, and a 2 times higher risk of developing late AMD. Pseudodrusen should be considered in evaluating the risk of late AMD development; however, due to considerable heterogeneity across these studies, a larger study is needed to validate these findings.

Reticular Pseudodrusen: A Risk Factor for Geographic Atrophy in Fellow Eyes of Individuals with Unilateral Choroidal Neovascularization

To determine whether reticular pseudodrusen (RPD) confer an increased risk of progression to late-stage age-related macular degeneration (AMD) in fellow eyes of those recently diagnosed with unilateral choroidal neovascularization (CNV). Retrospective study. Two hundred consecutive participants with CNV secondary to AMD in 1 eye and no signs of late-stage AMD in the fellow eye. Clinical examination and comprehensive retinal imaging, including spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and color fundus photography, at baseline and every follow-up visit. Incidence of geographic atrophy (GA) and CNV in the fellow eye. Mean age ± standard deviation was 77±7 years, and 61% of the cohort were female. Fifty-eight percent (n= 116) had RPD, 68% had drusen of 125 μm or more, 36% had pigmentary changes, 10% had both drusen of 125 μm or more and pigmentary changes, and 17% had only RPD in their fellow eyes. After a mean follow-up of 2.3 years, CNV developed in 36% of patients and GA developed in 14% of patients. Those with RPD demonstrated late-stage AMD (61% vs. 33.4%; P <0.001) and GA (22.4% with RPD vs. 2.4% without RPD; P <0.001) more often. The presence of reticular pseudodrusen was an independent risk factor for the development of GA (hazard ratio [HR], 4.93; P= 0.042), but not for CNV (HR, 1.19; P= 0.500), at least within the follow-up of this study. Both drusen of 125 μm or more and pigmentary changes at baseline were significant risk factors for the development of CNV and GA (HR, 1.96-11.73; P ≤0.020). Reticular pseudodrusen seem to confer an increased risk of progression to GA, in addition to drusen and pigmentary changes. The presence of RPD needs to be taken into account when discussing a patient's prognosis and planning management.

Incidence and Progression of Geographic Atrophy: Observations from a Population-based Cohort

To examine early age-related macular degeneration (AMD) lesion characteristics and risk factors associated with the long-term development and progression of geographic atrophy (GA). Population-based cohort. Of 3654 participants aged ≥49 years in the Blue Mountains Eye Study, 75.8%, 76.7%, and 56.1% of survivors attended the 5-, 10-, and 15-year follow-up examinations, respectively. Retinal photographs were taken at each visit. Incident GA was confirmed using a side-by-side grading method. Computer planimetry was used to measure the area involved by GA. Fast and slow/normal progression rates were defined as GA area enlargement by ≥2 and <2 mm(2)/year, respectively. Incident GA was estimated using the Kaplan-Meier product-limit method. Early AMD lesion characteristics were assessed for association with GA incidence using eye-specific data and generalized estimating equation models adjusting for age, current smoking, and presence of risk alleles of the complement factor H (CFH) or age-related maculopathy susceptibility 2 (ARMS2) genes, genotyped or imputed using genome-wide scan data. Incidence and progression of GA. By excluding 41 subjects with GA at baseline, of 2503 participants at risk of GA, incident pure GA (without coexisting neovascular AMD lesions) was confirmed in 57 participants, with a 15-year incidence of 3.6%. Baseline early AMD lesion characteristics associated with GA incidence included drusen type (soft indistinct: odds ratio [OR], 59.0; 95% confidence interval [CI], 20.4-171.0; reticular drusen: OR, 13.9; 95% CI, 4.0-47.6); drusen location within a 500-μm radius of the fovea (OR, 15.1; 95% CI, 7.4-30.8); drusen area greater than 375 μm in diameter (OR, 10.1; 95% CI, 4.0-25.6); presence of retinal pigment epithelial depigmentation (OR, 9.0; 95% CI, 4.1-19.8); or hyperpigmentation (OR, 12.0; 95% CI, 6.1-23.5), referenced to subjects with no or hard drusen only. Fast progression was more frequent among current smokers at baseline, subjects with the CFH or ARMS2 risk genotypes, and pseudophakic eyes. Early AMD lesion characteristics (type, location, area involved) were strongly associated with higher long-term risk of developing GA independent of age, smoking, and AMD genetic susceptibility from the CFH or ARMS2 genes. Known AMD risk factors also were more frequently present among quickly progressing GA cases. Proprietary or commercial disclosure may be found after the references.

Characteristics of Incident Geographic Atrophy in the Complications of Age-Related Macular Degeneration Prevention Trial

To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). Retrospective cohort study within a larger clinical trial. Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during 5 to 6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA.(23) Color-optimized fundus photographs were viewed concurrently with the FAs during grading. Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. At presentation, the median total GA area was 0.26 mm(2) (0.1 disc area). Geographic atrophy presented as a single lesion in 89 (78%) eyes. The median distance from the fovea was 395 μm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 μm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline VA level compared with 1 letter among matched early age-related macular degeneration eyes without GA. Geographic atrophy that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm(2); P = 0.0001), were more central (50 vs. 500 μm from the center of the fovea; P<0.0001), and were associated with significantly worse visual outcome (20/50 vs. 20/25; P = 0.0003) than GA with other drusen types as precursors. Incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA vary with precursor drusen types. These data can facilitate design of future clinical trials of therapies for GA. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dietary Omega-3 Fatty Acids, Other Fat Intake, Genetic Susceptibility, and Progression to Incident Geographic Atrophy

To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA). Observational analysis of a prospective cohort. A total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not. Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA. Associations between dietary fat intake reported from FFQs, genetic variants, and incident GA. Increased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (P trend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90). Increased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Association of Aspirin Use With Age-Related Macular Degeneration

To determine whether regular aspirin use is associated with a higher risk for developing age-related macular degeneration (AMD) by using analyzed data from a 15-year prospective cohort. A prospective analysis was conducted of data from an Australian population-based cohort with 4 examinations during a 15-year period (1992-1994 to 2007-2009). Participants completed a detailed questionnaire at baseline assessing aspirin use, cardiovascular disease status, and AMD risk factors. Age-related macular degeneration was graded side-by-side from retinal photographs taken at each study visit to assess the incidence of neovascular (wet) AMD and geographic atrophy (dry AMD) according to the international AMD classification. Of 2389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of the 2389 developed neovascular AMD. Persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjustment for age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index, persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25-4.83). The association showed a dose-response effect (multivariate-adjusted P = .01 for trend). Aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59-1.65). Regular aspirin use is associated with increased risk of incident neovascular AMD, independent of a history of cardiovascular disease and smoking.

Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents

Objective To examine risk factors for incident age-related macular degeneration (AMD) after combining data from 3 population-based cohort studies. Design Population-based cohort study. Population A population of 9523 adults (age range, 43–95 years at baseline) living in Australia, The Netherlands, and the United States who participated in a baseline examination and a follow-up examination on average 5 or 6 years later. Methods Similar procedures were used at all study sites. Examinations included a standardized questionnaire, pupillary dilation, and stereoscopic color fundus photography. Fundus photographs were graded for lesions associated with AMD using the Wisconsin and International Age-Related Maculopathy Grading Systems. Senior investigators from each site adjudicated all photos graded as late AMD. Main outcomes measure Incidence of late AMD. Results Among studies, distributions for most risk factors differed, and overall incidence rates were similar. In the Beaver Dam Eye Study, total serum cholesterol was inversely associated with incident neovascular AMD. In the Blue Mountains Eye Study, current smoking (defined as smoking at the time of the baseline examination) was associated with an increased risk of incident geographic atrophy and late AMD; increased total serum cholesterol, having diabetes, and older age at menopause were positively associated with incident geographic atrophy; and an increase in high-density lipoprotein serum cholesterol was inversely related to incident geographic atrophy. In the Rotterdam Study, current smoking was associated with an increased risk of incident geographic atrophy, neovascular AMD, and late AMD; past smoking was associated with an increased risk of incident neovascular AMD and late AMD; and an increased number of years between menarche and menopause was directly related to incident geographic atrophy. After pooling data, the only statistically significant relationships found were between smoking and total serum cholesterol and incident AMD. Current smoking was associated with an increased incidence of geographic atrophy and late AMD (odds ratios [ORs] relative to nonsmokers: 2.83 and 2.35, respectively; ORs relative to past smokers: 2.80 and 1.82, respectively), and total serum cholesterol was associated directly with incident geographic atrophy (OR: 1.08 per 10 mg/dl) and inversely with incident neovascular AMD (OR: 0.94 per 10 mg/dl). Conclusions Pooled data support a growing body of evidence indicating that smoking is related to an increased risk of incident AMD. Current smokers were at higher risk of incident AMD than both past smokers and those who never smoked. The relationships found in this study between total serum cholesterol and incident geographic atrophy and neovascular AMD are not readily explained.

The association of cardiovascular disease with the long-term incidence of age-related maculopathy: The beaver dam eye study

Purpose To examine the association between cardiovascular disease and its risk factors and the 10-year incidence of age-related maculopathy. Design Population-based cohort study. Participants Persons 43 to 86 years of age at baseline examination from 1988 to 1990, living in Beaver Dam, Wisconsin, of whom 3684 persons participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up examination. Methods Standardized protocols for physical examination, blood collection, administration of a questionnaire, and stereoscopic color fundus photography to determine age-related maculopathy. The Kaplan–Meier (product–limit) survival approach and discrete linear logistic regression were used in the data analysis. Main outcome measures Incidence and progression of age-related maculopathy. Results When age, gender, and history of heavy drinking, smoking, and vitamin use were controlled for, higher systolic blood pressure at baseline was associated with the 10-year incidence of retinal pigment epithelial depigmentation (risk ratio [RR] per 10 mmHg systolic blood pressure, 1.10; 95% confidence interval [CI], 1.01–1.18; P = 0.02) and exudative macular degeneration (RR, 1.22; 95% CI, 1.06–1.41; P = 0.006). Higher pulse pressure at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR per 10 mmHg, 1.17; 95% CI, 1.07–1.28; P < 0.001), increased retinal pigment (RR, 1.10; 95% CI, 1.01–1.19; P = 0.03), exudative macular degeneration (RR, 1.34; 95% CI, 1.14–1.60; P < 0.001), and progression of age-related maculopathy (RR, 1.08; 95% CI, 1.01–1.17; P = 0.03). Higher serum high-density lipoprotein cholesterol at baseline was associated with pure geographic atrophy (RR per 10 mg/dl high-density lipoprotein cholesterol, 1.29; 95% CI, 1.05–1.58; P = 0.01). Physical activity at baseline was associated with the incidence of geographic atrophy (RR in those who worked up a sweat 5 times a week compared with those who did not, 0.12; 95% CI, 0.02–0.91; P = 0.04) exudative macular degeneration (RR, 0.27; 95% CI, 0.08−0.87; P = 0.05), and progression of age-related maculopathy (RR, 0.69; 95% CI, 0.47–1.00; P = 0.05). Neither a history of stroke nor heart attack was associated with the incidence or progression of age-related maculopathy. Conclusions These findings indicate relationships between higher pulse pressure (a presumed indicator of age-related elastin and collagen changes in Bruch’s membrane) and systolic blood pressure with an increased 10-year incidence of some lesions defining early age-related maculopathy and exudative macular degeneration.

Laser treatment in fellow eyes with large drusen: updated findings from a pilot randomized clinical trial

Purpose To update the findings from the Choroidal Neovascularization Prevention Trial (CNVPT) with respect to resolution of drusen, incidence of choroidal neovascularization, and visual function. Design A multicenter, randomized, controlled, pilot clinical trial. Participants The 120 patients enrolled in the CNVPT. Patients had signs of choroidal neovascularization or retinal pigment epithelial detachment in 1 eye and had ≥10 large (>63-μm) drusen in the contralateral, or fellow, eye. Intervention The fellow eye of 59 patients was assigned randomly to argon green laser treatment consisting of multiple 100-μm spots at least 750 μm from the center of the fovea. The fellow eye of the remaining 61 patients was assigned randomly to observation. Main outcome measures Change in visual acuity was the primary outcome measure. Incidence of choroidal neovascularization, resolution of drusen, change in contrast threshold, change in critical print size for reading, and incidence of geographic atrophy were secondary outcome measures. Results Throughout 4 years of follow-up, there were no statistically significant differences in change in visual acuity, contrast threshold, critical print size, or incidence of geographic atrophy. With additional follow-up, the large increase in the incidence of choroidal neovascularization observed within 18 months of treatment was maintained; however, by 30 months, the incidence in the two treatment groups was the same. Most drusen resolution in treated eyes occurred within 24 months of the initial treatment. Treated eyes that received higher-intensity laser burns had an increased risk of choroidal neovascularization. Among eyes developing choroidal neovascularization in each treatment group, most lesions (two thirds or more) were composed of occult neovascularization only. Conclusions Laser treatment as applied in the CNVPT caused an excess risk of choroidal neovascularization in the first year or so after treatment. The increased early incidence of choroidal neovascularization was not associated with either a harmful or beneficial effect in this pilot study.